tbuckley/cabot-search huggingface dataset:
Abstract 755: The impact of cancer treatment on cognitive function and quality of life in patients undergoing treatment at a tertiary care hospital in New Delhi, India
Authors: Delfin Lovelina Francis
Journal: Cancer Research (2023)

Abstract Background: Cognitive dysfunction is becoming a more well-known complication of cancer and its treatment. Cancer-related cognitive changes and impairment have also been documented in non-central nervous system (non-CNS) cancer patients. The majority of research in this area has discovered that a subset of patients appear to be vulnerable to this complication even after treatment has ended, and they frequently struggle with multitasking, short-term memory, word-finding, attention, or concentration. It is critical to investigate the possible link between cancer and cognitive impairment because it can have a serious impact on quality of life. Methods: This cross-sectional study between May 2022 and October 2022, included patients who were referred to the dental outpatient department as part of a preventive/prophylactic evaluation at the tertiary care centre in New Delhi, India. After receiving informed consent, the oral health impact profile-14 instrument to assess participants' oral health-related quality of life (OHRQoL) and the Montreal Cognitive Assessment (MOCA) for cognitive evaluation were used. Results: Out of 283 patients 77% males and 23% females and vast majority had Stage III cancer. All patients' OHRQoL was hampered, but it was higher in those who developed visible oral changes during treatment versus those who did not (P =.001). Taking painkillers, losing sexual interest, difficulty in social contact, loss of taste and smell senses were the main factors affecting oral health related QoL (OHRQoL). A significant relationship was discovered between pain, speech, social eating, dry mouth, sticky saliva, and weight loss in relation to various treatment modalities. Those who were treated surgically alone had better QoL than others, according to the OHRQoL scores. In terms of delayed recall, 55% were found to be cognitively impaired, which was associated with lower OHRQoL. Conclusion: Cognitive impairment is common in cancer patients, which may be caused by the cancer itself. It is also linked to OHRQoL and psychosocial variables. There has been little research into the relationships between cognitive function and quality of life (OHRQoL) in cancer patients. Together with previous research indicating that cognitive function and OHRQoL can influence treatment adherence and outcomes, the findings support the inclusion of cognitive screening and OHRQoL assessment as part of patient pretreatment assessment. Citation Format: Delfin Lovelina Francis. The impact of cancer treatment on cognitive function and quality of life in patients undergoing treatment at a tertiary care hospital in New Delhi, India [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 755.
Abstract 6018: Sequencing of 5-hydroxymethylcytosine to single base resolution
Authors: Daniel J. Evanich, V. K. Chaithanya Ponnaluri, Vaishnavi Panchapakesa, Ariel Erijman, Matthew A. Campbell, Nan Dai, Bradley W. Langhorst, Romualdas Vaisvila, Louise Williams
Journal: Cancer Research (2023)

Abstract DNA methylation is an epigenetic regulator of gene expression with important functions in development and diseases such as cancer. The modified cytosines, 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are identified using Illumina sequencing. Libraries are generated using either NEBNext® EM-seq™, an enzyme-based workflow, or by using sodium bisulfite conversion. These methods, however, cannot differentiate between 5mC and 5hmC. Distinguishing these modifications is important as there is increased interest in 5hmCs role in regulating gene expression. Methods currently exist to enable discrimination of 5mC and 5hmC, for example, oxBS-seq and TAB-seq. These methods still rely upon sodium bisulfite conversion and have reduced data quality due to fragmentation and loss of DNA. Here we describe an enzymatic method that enables specific detection of 5hmC. 5hmC is detected using two enzymatic steps. Firstly, 5hmCs are glucosylated, which protects them from subsequent deamination by APOBEC. In contrast, cytosines and 5mCs are deaminated resulting in their conversion to uracil and thymine, respectively. During Illumina sequencing deaminated cytosine and 5mC are read as thymine and the glucosylated 5hmC are read as cytosine. Subtractive analysis of 5hmC data from EM-seq data, which detects both 5mC and 5hmC, permits the identification of individual 5mC and 5hmC sites. 5hmC data were generated for inputs of 0.1 ng to 200 ng DNA isolated from E14 mouse embryonic stem cells and human brain. The 5hmC libraries had similar characteristics to EM-seq libraries, including expected insert sizes due to intact DNA molecules, low duplication rates and minimal GC bias. T4147 phage DNA was used as an internal control, as all cytosines are 5-hydroxymethylated, with 98-99% of cytosines identified as 5hmC. 5mC and 5hmC levels were also profiled during E14 cell differentiation for 10 days. Interestingly, 5hmC levels decreased whereas 5mC levels increased particularly during the first five days of differentiation. LC-MS/MS quantification of this same DNA mirrored the changes observed by sequencing. The ability to discriminate between 5mC and 5hmC will provide key insights into the role of these cytosine modifications in development and disease. Citation Format: Daniel J. Evanich, V. K. Chaithanya Ponnaluri, Vaishnavi Panchapakesa, Ariel Erijman, Matthew A. Campbell, Nan Dai, Bradley W. Langhorst, Romualdas Vaisvila, Louise Williams. Sequencing of 5-hydroxymethylcytosine to single base resolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6018.
Abstract 2417: Liver regeneration after radiation therapy: clinical observations and a new rat model
Authors: Tingshi Su, Weidong Zhao, qing Li, Qiaoyuan Wu
Journal: Cancer Research (2023)

Abstract Background and Purpose: Radiation-induced liver damage, a dose-limiting complication of radiotherapy for liver tumors, has been focused mainly on prevention and treatment but has largely ignored the molecular mechanisms underlying the liver’s regenerative capacity after irradiation. Whether liver regeneration compensates for radiation-induced liver damage is of great clinical significance. This study aims to observe clinical liver regeneration and the potential molecular mechanism in rat models after irradiation. Methods: To stimulate the liver regeneration response, we delineated a liver protection area in the patient’s normal liver to protect it from excessive irradiation, and designed a rat model in which large single fractions of 25 Gy or 15 Gy of radiation were delivered to 1/2 or 2/3 of the total liver volume to investigate liver regeneration after irradiation. We used proteomics analysis and western blotting assays to investigate liver regeneration signaling and molecular mechanisms. Results: Four patients’ pairs of liver specimens from areas of high irradiation and regeneration (protected liver) were collected. Proteomics analysis showed enrichment in several pathways, with some of the greatest changes observed in PI3K-Akt signaling, further confirmed in liver-irradiated rat models. After irradiation, the liver injury index was significantly elevated on day-1 and gradually recovered to normal levels by day-8 in rat models. The model of a single 25-Gy fraction delivered to half of the liver volume best represented the clinically similar phenomenon of liver regeneration in the protected liver. We tested the effects of an Akt/mTOR activator (carbamazepine), which enhanced regeneration, and an Akt/mTOR inhibitor (temsirolimus), which inhibited regeneration. Finally, liver regeneration was enhanced in rats treated with temsirolimus followed by carbamazepine. Conclusions: Our results suggest that protecting the normal liver outside the irradiated area enhances the probability of successful regeneration to compensate for radiation-induced liver injury. PI3K/AKT/mTOR is essential in liver regeneration after irradiation, and carbamazepine may enhance liver regeneration after irradiation in rats. Citation Format: Tingshi Su, Weidong Zhao, qing Li, Qiaoyuan Wu. Liver regeneration after radiation therapy: clinical observations and a new rat model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2417.
Abstract 3903: Role of the miR-301a/Fra-2/GLIPR1 axis in lung cancer cisplatin resistance
Authors: Francesca Lovat, Gian Luca Rampioni Vinciguerra, Marina Capece, Rosario Distefano, Giovanni Nigita, Andrea Vecchione, Carlo M. Croce
Journal: Cancer Research (2023)

Abstract Lung cancer is the leading cause of cancer-related mortality in both men and women worldwide. Despite the administration of platinum compounds represents the main treatment, the majority of tumors remains intrinsically resistant. In lung cancer, miR-301a exerts a main role by modulating the activity of transcription factors like NF-kB and Stat3. Here, we dissected the contribution of miR-301a in the regulation of its new identified target Fos-related antigen-2 (Fra-2), a transcription factor that belongs to the Fos/AP-1 family. By microarray analysis, we discovered that Fra-2 overexpression increased glioma pathogenesis-related protein 1 (GLIPR1) levels, a mediator of cisplatin resistance in lung cancer. Its mechanism of regulation is still unclear. We demonstrated that GLIPR1 is also a miR-301a target. In vitro, modulation of miR-301a reduced Fra-2 and GLIPR1 levels; conversely, Fra-2 overexpression significantly increased GLIPR1 and miR-301a. Then, by chromatin immunoprecipitation assay, we confirmed that Fra-2 interacts with the promoter regions of both GLIPR1 and MIR301A genes, supporting that miR-301a/Fra-2/GLIPR1 axis could be autoregulated by feedback loop in which Fra-2 promotes the transcription of MIR301A gene. Investigating the effect of this new axis on the response to cisplatin, we observed that both Fra-2/GLIPR1 overexpression and miR-301a silencing induced cisplatin resistance in lung cancer cells. By contrast, silencing of GLIPR1 and combined administration of low doses of Fos/AP-1 inhibitor restored the cisplatin sensitivity in Fra-2 overexpressing cells. In the lung adenocarcinoma samples from the TCGA dataset, miR-301a overexpression inversely correlated with Fra-2 and GLIPR1 expression. Consistently, the overexpression of miR-301a identified a fraction of tumors with low expression of Fra-2 and GLIPR1 in an internal cohort of lung cancer samples. Altogether, our findings identify the miR-301a/Fra-2/GLIPR1 axis that contributes to cisplatin resistance in lung cancer cells and could serve as biomarker to stratify patients who may benefit from cisplatin administration, alone or in combination with Fos/AP-1 inhibitors. Citation Format: Francesca Lovat, Gian Luca Rampioni Vinciguerra, Marina Capece, Rosario Distefano, Giovanni Nigita, Andrea Vecchione, Carlo M. Croce. Role of the miR-301a/Fra-2/GLIPR1 axis in lung cancer cisplatin resistance. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3903.
Abstract 2752: Targeting intracellular tumor antigens using fully human TCR mimic antibodies derived from HLA transgenic RenMiceTM
Authors: Jun Du, Taolin Liu, Wanbo Tang, Yue Zhang, Limin Zhao, Xin Jiao, Chao Sun, Pengfei Du, Yuqi Zhang, Baihong Liu, Qingcong Lin, Yi Yang
Journal: Cancer Research (2023)

Abstract Therapeutic antibodies have ushered in a new age of cancer immunotherapy. Historically, these therapies have targeted a limited subset of soluble and cell surface tumor-associated antigens (TAAs). T cell receptors (TCRs) on cytotoxic CD8+ T cells recognize peptide antigens bound to major histocompatibility class I (MHC-I) proteins, called HLA-A/B/C in humans. By this pathway, antigen is regularly sampled from the intracellular peptidome, processed, and presented to cytotoxic T cells. Expanding TCR-based recognition of soluble, intracellular TAAs presented on the surface of malignant cells by this mechanism is a propitious therapeutic strategy. Here we describe a novel platform for generating T cell receptor mimic (TCRm) antibodies using our humanized immunoglobulin (RenMabTM) mice engineered to express HLA. TCRm antibodies have the same binding properties as endogenous TCRs and recognize processed, HLA-bound peptides including intracellular tumor-associated antigens, viral oncoproteins, and cancer-testis antigen (CTA). TCRm antibodies bind peptide-HLA with high specificity and up to nanomolar affinity. Our optimized immunization protocols and high-throughput screening methods allow for one-step TCRm antibody generation. TCRm antibodies can also be used to assemble bispecific T cell engaging antibodies (BiTEs) to enhance tumor targeting of cytotoxic T cells. Biocytogen’s TCRm antibodies are a flexible and powerful tool for cancer immunotherapy. By enabling TCR-mediated recognition of an unrestricted repertoire of cancer neoantigens, TCRm antibodies may find broad clinical application. Citation Format: Jun Du, Taolin Liu, Wanbo Tang, Yue Zhang, Limin Zhao, Xin Jiao, Chao Sun, Pengfei Du, Yuqi Zhang, Baihong Liu, Qingcong Lin, Yi Yang. Targeting intracellular tumor antigens using fully human TCR mimic antibodies derived from HLA transgenic RenMiceTM [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2752.
Abstract 5918: Interrogating host-intratumoral microbial interactions in pancreatic cancer
Authors: Vidhi Chandra, Hajar Rajaei, Seyda Baydogan, Javier Gomez, Sammy Ferri-Borgogno, Anirban Maitra, Erick Riquelme, Ismet Sahin, Jared Burks, Michael Kim, Florencia McAllister
Journal: Cancer Research (2023)

Abstract Cancer is increasingly becoming a rising cause of mortality worldwide. Microbiota, both within the gut and tumors, has emerged as a significant player influencing tumor growth and responses to therapies. The tumor niche provides a privileged microenvironment for microbial colonization. Recent evidence links microbiota and pancreatic tumorigenesis. Pancreatic ductal adenocarcinoma (PDAC), is an aggressive cancer surrounded by a highly immuno-suppressive tumor microenvironment (TME) which limits efficacy of most available therapies. We have previously reported that rare long-term survival in pancreatic cancer is associated with an intratumoral microbial signature which correlates with enhanced TME immunoactivation, suggestive of microbial mediated immune cell recruitment. A gut-to-tumor microbial crosstalk was also found in a human-to-mouse Fecal Microbiota Transplant (FMT) tumor model. While we have identified the vital role of microbiota in affecting tumor immunity, there is still a gap of knowledge about local microbial interactions within TME. Deeper understanding of the microbial mediated events that are triggered and follow PDAC development, which act to induce and support tumor growth, would provide us with potential novel targets that could be blocked to reverse PDAC immunosuppression and tumor growth. To interrogate the features of the pancreatic tumor microbial niche, we performed spatial co-detection of microbial and host targets to identify the cellular compartment which interacts with microbes inside the TME in clinical samples. We developed novel qualitative and quantitative imaging methodologies for evaluating crosstalk between the host and microbes. We also evaluated the effect of microbial burden on transcriptomic changes in host cells through multiple spatial sequencing approaches. Overall, we dissect the functional role of microbes in orchestrating TME organization and their effect on tumor signaling. Citation Format: Vidhi Chandra, Hajar Rajaei, Seyda Baydogan, Javier Gomez, Sammy Ferri-Borgogno, Anirban Maitra, Erick Riquelme, Ismet Sahin, Jared Burks, Michael Kim, Florencia McAllister. Interrogating host-intratumoral microbial interactions in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5918.
Abstract 3317: Expression of glucose transporter-1 in follicular lymphoma affected tumor-infiltrating immunocytes and was related to progression of disease within 24 months
Authors: Jianli Ma, Yuwei Deng, Shu Zhao, Ming Yang, Yutian Yu, Qingyuan Zhang, Jinming Yu
Journal: Cancer Research (2023)

Abstract Objective Follicular lymphoma (FL) occurring progression within 24 months (POD24) after initial immunochemotherapy has poor prognosis. GLUT1 affects glycolysis within tumor microenvironment (TME) and promotes tumor progression. However, its specific mediated mechanism remains unclear in FL. Methods Baseline GLUT1 expression, infiltrations of M2 macrophage, and CD8+ T-cells were assessed by immunohistochemistry in FL with POD24 and long-term remission respectively. The spatial features of TME were assessed by MIBI-TOF and proteomics. Predictive immunophenotypes for POD24 occurrence was analyzed by random forest algorithm. The lactate production and the induction of M2 macrophages were detected when GLUT1 was transfected or knocked down in DOHH2. The activation of PI3K/Akt/mTOR signaling in DOHH2 and WSU-FSCCL cells co-cultured with induced inhibitory immunocytes was tracked by western blotting. Results The FL with POD24 exhibited higher baseline GLUT1 expression and increased infiltration of various inhibitory immunocytes. Spatial signatures of 69 immunophenotypes could predict POD24 occurrence. The activation of PI3K/Akt/mTOR signaling pathway was not significant in both groups. The supernatant of DOHH2-GLUT1 cells which had more lactate content could induce more M2-type macrophages than that of DOHH2/siRNA GLUT1 cells. When co-cultured with exhausted CD8+ T cells, M2-type macrophages and Tregs, compared with WSU-FSCCL cells, DOHH2 cells with high GLUT1 expression induced more M2-type macrophages and was triggered activation of PI3K/Akt/mTOR signaling pathway. Conclusion Tumor cells overexpressing GLUT1 could domesticate immunocytes to form an immunosuppressive TME, which promotes occurrence of POD24 and gradually activates PI3K/Akt/mTOR pathway of tumor cells in FL. Clinical correlation between GLUT1 expression and tumor-infiltrating macrophages and CD8+ T cells GLUT1 expression High n(%) Low n(%) P value CD206 expression High 16(43.2) 5(18.5) 0.037 Low 21(56.8) 22(81.5) CD8 expression High 27(73.0) 12(44.4) 0.021 Low 10(27.0) 15(55.6) Citation Format: Jianli Ma, Yuwei Deng, Shu Zhao, Ming Yang, Yutian Yu, Qingyuan Zhang, Jinming Yu. Expression of glucose transporter-1 in follicular lymphoma affected tumor-infiltrating immunocytes and was related to progression of disease within 24 months [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3317.
Abstract 3995: Trastuzumab deruxtecan, antibody-drug conjugate targeting HER2, effectively inhibits growth of patient-derived xenograft model with CIC-rearranged sarcoma
Authors: Yuki Kojima, Shigehiro Yagishita, Kazuki Sudo, Tatsunori Shimoi, Shintaro Iwata, Shun-ichi Watanabe, Chitose Ogawa, Akihiko Yoshida, Yasushi Yatabe, Kan Yonemori, Akinobu Hamada
Journal: Cancer Research (2023)

Abstract Background: Capicua-double homeobox 4 (CIC-DUX4)-rearranged sarcomas (CDS) are extremely rare and highly aggressive sarcomas. There is no standard therapy for the patients with advanced CDS, and therapeutic development is needed. We evaluated preclinical efficacy of trastuzumab deruxtecan (T-DXd), a humanized monoclonal HER2-targeting antibody conjugated to a topoisomerase 1 inhibitor, DXd, in patient-derived xenograft (PDX) models with CDS. Methods: Patient-derived tumor tissue was transplanted into subcutaneous around the flank of female NOG mice, which were treated with vehicle or T-DXd (3 mg/kg, intravenous, Day0) when the mean tumor volume reached 200 mm3. Tumor volume was assessed twice weekly for 3 weeks to assess the efficacy of T-DXd. Results: This study included 3 CDS-derived PDXs. HER2 expression was low in one PDX and not expressed in two PDXs. One PDX was established from a specimen at initial diagnosis, two were established from specimens after prior-chemotherapy. T-DXd demonstrated significant tumor growth delay compared to vehicle in all PDX models investigated. One PDX with no efficacy was HER2-negative and had a treatment history of topoisomerase I inhibitor. In contrast, PDX of HER2-negative topoisomerase I inhibitor-resistant Ewing sarcoma was also administered T-DXd under the same conditions and was found to be refractory. Conclusion: The present study showed that a therapeutic potential of T-DXd in CDS patients, including HER2-negative. Citation Format: Yuki Kojima, Shigehiro Yagishita, Kazuki Sudo, Tatsunori Shimoi, Shintaro Iwata, Shun-ichi Watanabe, Chitose Ogawa, Akihiko Yoshida, Yasushi Yatabe, Kan Yonemori, Akinobu Hamada. Trastuzumab deruxtecan, antibody-drug conjugate targeting HER2, effectively inhibits growth of patient-derived xenograft model with CIC-rearranged sarcoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3995.